Receptors for 5-hydroxytryptamine on the sympathetic nerves of the rabbit heart
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The Langendorff perfused rabbit heart has been used to investigate the effects of 5-hydroxytryptamine (5-HT) and several closely related analogues as stimulants and inhibitors of transmitter release from the terminal cardiac sympathetic nerves.
Sympathomimetic responses to 5-HT were unaffected by perfusion of hearts with hexamethonium at a concentration which abolished responses to DMPP and by perfusion with morphine or methysergide unless high concentrations were used.
Bolus injections of 5,6-dihydroxytryptamine, 5,7-dihydroxytryptamine, α-methyl-5-HT, N-methyl-5-HT, N,N-dimethyl-5-HT, tryptamine, N-methyltryptamine and N,N-dimethyltrytamine also evoked sympathomimetic responses on rabbit heart; 5-methoxytryptamine, 5-methoxy-6-hydroxytryptamine, N,N-dimethyl-5-methoxytryptamine, 5-methyltryptamine and α-methyltryptamine were without effect at doses up to 512 μg.
Cardiac stimulant responses to all the compounds were markedly inhibited by perfusion of hearts with propranolol (100 ng/ml) and, with the exception of α-methyl-5-HT and N-methyltryptamine, by colchicine (400 μg/ml). During perfusion with 5-HT (1.25 μg/ml) responses to 5-HT, 5,6-dihydroxytryptamine, 5,7-dihydroxytryptamine, N-methyl-5-HT and tryptamine were abolished; residual responses remained to α-methyl-5-HT, N,N-dimethyl-5-HT, N-methyltryptamine and N,N-dimethyltryptamine.
5-HT and all the analogues except N,N-dimethyl-5-methoxytryptamine stimulated the guinea pig ileum to contract both in the presence of methysergide, 1 μg/ml, (residual responses blocked by morphine plus atropine, therefore indirect cholinergic) and in the presence of atropine, 1 μg/ml, plus morphine sulphate, 1 μg/ml (residual responses blocked by methysergide, therefore direct action on the smooth muscle).
Equiactive molar ratios of potency were obtained on heart and ileum. In general the relative potencies of the compounds as cardiac stimulants were more similar to the values obtained on the ileum treated with methysergide than on the ileum treated with atropine plus morphine, although 5-methoxytryptamine was a notable exception to this generalisation.
Perfusion of hearts with low concentrations of 5-HT (78 and 312 ng/ml) caused inhibition of the cardiac stimulant responses to bolus injections of 5-HT. The effect was selective in that responses to noradrenaline and DMPP were unaffected.
5,6-Dihydroxytryptamine, 5,7-dihydroxytryptamine, α-methyl-5-HT, N-methyl-5-HT, N,N-dimethyl-5-HT, tryptamine and N,N-dimethyltryptamine proved also to be selective antagonists of the cardiac stimulant response to 5-HT. The order of potency as antagonists of 5-HT was similar to the order of potency as stimulants of the cardiac sympathetic nerves.
5-Methoxytryptamine, N,N-dimethyl-5-methoxytryptamine, α-methyltryptamine, N-methyltryptamine and 5-methyltryptamine were weak antagonists of 5-HT. The antagonism was non-selective since responses to DMPP were also reduced.
The results suggest that several analogues of 5-HT have the capacity both to stimulate and to inhibit transmitter release from the sympathetic nerves of the rabbit heart in a manner similar to 5-HT itself. The mechanism involves selective neuronal receptor sites which in terms of agonist relative potencies are more similar to the receptors of the cholinergic neurones of the guinea pig ileum than the smooth muscle cells.
Key wordsCardiac sympathetic nerves 5-Hydroxytryptamine analogues Transmitter release Guinea pig ileum Cholinergic nerves
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